Bone marrow dysfunction presenting with abnormal hematopoietic cell growth is seen in AIDS. Since hematopoiesis is regulated by growth factors present in the BM microenvironment, this dysfunction may be related to an alteration of cytokine production, and this dysfunction may change as disease progresses. The goal of the proposed studies is to identify the mechanism of bone marrow dysfunction in HIV-infected individuals in order to determine whether these defects can be reversed, and to allow development of specific therapies to prevent aberrant bone marrow hematopoietic cell growth and development. To accomplish this goal, we will focus on the effect of HIV on bone marrow stromal cells, the population responsible for the hematopoietic microenvironment. Based on the hypothesis that HIV-infected bone marrow stromal cells have altered cell function, particularly in the production of specific growth factors, we will use stromal cell cultures to identify and functionally characterize marrow stromal cells from patients with HIV infection, and to determine the presence of HIV in the stromal population. The functional assays for cytokine production will include expression of protein for specific growth factors, quantitation of cytokines in supernatant using the ELISA assay, and their capacity to support colony-forming cells in methyl cellulose. To determine whether functional changes observed in patient stromal cells are due to direct or indirect effects of HIV infection, normal stromal cells will be exposed to inactivated virus, gp120 (the viral envelope protein), or intact HIV, and examined for growth factor production. These experiments are designed to determine: (1) the identity of the HIV target cells; (2) the changes in cytokine production during disease progression; (3) the mechanisms of viral alteration of bone marrow stromal cells. Understanding the role of HIV in altering the bone marrow microenvironment will lead to new therapeutic modalities to inhibit or reverse the effects of viral infection.